Dynamic protein S-palmitoylation is critical for neuronal function, development, and synaptic plasticity. Synaptic activity–dependent changes in palmitoylation have been reported for a small number of proteins. Here, we characterized the palmitoylome in the hippocampi of male mice before and after context-dependent fear conditioning. Of the 121 differentially palmitoylated proteins identified, just over half were synaptic proteins, whereas others were associated with metabolic functions, cytoskeletal organization, and signal transduction. The synapse-associated proteins generally exhibited increased palmitoylation after fear conditioning. In contrast, most of the proteins that exhibited decreased palmitoylation were associated with metabolic processes. Similar results were seen in cultured rat hippocampal neurons in response to chemically induced long-term potentiation. Furthermore, we found that the palmitoylation of one of the synaptic proteins, plasticity-related gene-1 (PRG-1), also known as lipid phosphate phosphatase-related protein type 4 (LPPR4), was important for synaptic activity–induced insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) into the postsynaptic membrane. The findings identify proteins whose dynamic palmitoylation may regulate their role in synaptic plasticity, learning, and memory.

The World Health Organization 2021 classification introduces molecular grading criteria for anaplastic meningiomas, including TERT promoter (TERTp) mutations and CDKN2A/B homozygous deletion. Additional adverse prognostic factors include H3K27me3 and BAP1 loss. The aim of this study was to explore whether these molecular alterations stratified clinical outcomes in a single-center cohort of grade 3 meningiomas. Additionally, we examined whether p16 and MTAP immunohistochemistry can predict CDKN2A/B status. Clinical and histopathological information was obtained from the electronic medical records of grade 3 meningiomas resected at a tertiary center between 2007 and 2020. Molecular testing for TERTp mutations and CDKN2A/B copy-number status, methylation profiling, and immunohistochemistry for H3K27me3, BAP1, p16, and methylthioadenosine phosphorylase (MTAP) were performed. Predictors of survival were identified by Cox regression. Eight of 15 cases demonstrated elevated mitotic index (≥20 mitoses per 10 consecutive high-power fields), 1 tumor exhibited BAP1 loss, 4 harbored TERTp mutations, and 3 demonstrated CDKN2A/B homozygous deletion. Meningiomas with TERTp mutations and/or CDKN2A/B homozygous deletion showed significantly reduced survival compared to anaplastic meningiomas with elevated mitotic index alone. Immunohistochemical loss of p16 and MTAP demonstrated high sensitivity (67% and 100%, respectively) and specificity (100% and 100%, respectively) for predicting CDKN2A/B status. Molecular alterations of grade 3 meningiomas stratify clinical outcomes more so than histologic features alone. Immunohistochemical loss of p16 and MTAP show promise in predicting CDKN2A/B status.

Background: Both Mediterranean and ketogenic diets have been proposed as nutritional interventions in Parkinson's disease (PD). Combined approaches may offer maximal benefits. Objective: Assess the feasibility, safety and exploratory efficacy of two ketogenic interventions, using a Mediterranean diet base, in individuals with PD (PwP). Methods: In this Phase II, random-order crossover study, PwP followed two 8-week dietary interventions, separated by an 8-week washout: 1) a high-fat, low-carbohydrate Mediterranean diet (MeDi-KD) and 2) a standard Mediterranean diet supplemented with medium chain triglycerides (MeDi-MCT). Results: Of 52 participants randomized, 48 started the trial. Forty-one (79%) participants completed at least one, whereas only 33 (63%) completed both intervention phases. There were no intervention-related serious adverse events, nor any significant changes in plasma lipid profiles. Seventy-three percent and 92% of participants reported deviating from the MeDi-KD and MeDi-MCT no more than a few times per month, respectively. Moderate Mediterranean Diet Adherence Screener scores of 6.7 (SD: 1.6) and 7.2 (SD: 2.3) were achieved during the MeDi-KD and MeDi-MCT, respectively, out of a maximum of 14. Fifty percent of participants were in nutritional ketosis ([beta-hydroxybutyrate] ([BHB]) > 0.5 mM) at follow-up for the MeDi-KD, as compared with only 1 (3%) participant following the MeDi-MCT. MDS-UPDRS Part II and IV scores decreased by a mean of −1.4 (SD: 4.2; p = 0.039) and −1.0 (SD: 3.0; p = 0.044) points, respectively, following the MeDi-MCT. Conclusions: While both Mediterranean-ketogenic interventions appear safe in the short-term in PwP, their feasibility is called into question by a high study dropout rate (37%) and modest adherence. Preliminary benefits observed in patient-reported motor experiences were paradoxically limited to the MCT-supplemented MeDi, in which ketosis was not reliably achieved. Together, our findings indicate the need to refine behavioral strategies to optimize dietary awareness and adherence in future trials. Trial Registration: The trial was registered on ClinicalTrials.gov: NCT05469997.

In the past few decades, neuropathology has experienced several paradigm shifts with the introduction of new technologies. Deep learning, a rapidly progressing subfield of machine learning, seems to be the next innovation to alter the diagnostic workflow. In this review, we will explore the recent changes in the field of neuropathology and how this has led to an increased focus on molecular features in diagnosis and prognosis. Then, we will examine the work carried out to train deep learning models for various diagnostic tasks in neuropathology, as well as the machine learning frameworks they used. Focus will be given to both the challenges and successes highlighted therein, as well as what these trends may tell us about future roadblocks in the widespread adoption of this new technology. Finally, we will touch on recent trends in deep learning, as applied to digital pathology more generally, and what this may tell us about the future of deep learning applications in neuropathology.

The 12-item Parkinson Anxiety Scale (PAS) assesses the severity of anxiety symptoms in people with Parkinson's disease (PwP). However, psychometric evidence supporting the English self-rated PAS remains largely limited to validation studies by the developers. This study aimed to reinforce validation of this scale through a comprehensive psychometric evaluation in PwP in Canada. Data were drawn from two Canadian samples of 130 and 53 PwP, respectively, at a tertiary center. Acceptability, reliability, validity, and factor structure were assessed. The Mini International Neuropsychiatric Interview was administered to confirm anxiety diagnoses. Optimal cut-off scores suggesting the presence of an anxiety disorder were determined using receiver operating characteristic (ROC) curve analysis. The PAS and its three subscales demonstrated good acceptability and internal consistency reliability (Cronbach's α > 0.70). Good convergent validity with the State-Trait Anxiety Inventory and divergent validity with scales assessing other non-motor symptoms were obtained. Confirmatory factor analysis supported the three-factor structure (comparative fit index = 0.987; Tucker-Lewis index = 0.983; root mean square error of approximation = 0.083; standardized root mean square residual = 0.087). Optimal cut-off scores were 12.5 for the total PAS (area under the ROC curve = 0.81, sensitivity = 0.89, specificity = 0.58), 8.5 for the persistent anxiety subscale, and 2.5 for the episodic anxiety and avoidance behavior subscales. Approximately 22 % of participants in the larger sample had a diagnosed anxiety disorder. The English self-rated PAS is a valid and reliable instrument for screening and assessing severity and dimensions of anxiety in PwP.